Molecular identification of aspartate N-acetyltransferase and its mutation in hypoacetylaspartia
| العنوان: | Molecular identification of aspartate N-acetyltransferase and its mutation in hypoacetylaspartia |
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| المؤلفون: | Gaëtane Noël, Mustapha Amyere, Marie-Cécile Nassogne, Pierre J. Courtoy, Elsa Wiame, Jonathan Desmedt, Marie-Françoise Vincent, Jean-Noël Octave, Eugen Boltshauser, Emile Van Schaftingen, Donatienne Tyteca, Nathalie Pierrot, Miikka Vikkula, François Collard |
| المساهمون: | University of Zurich, van Schaftingen, E |
| المصدر: | Biochemical Journal. 425:127-139 |
| بيانات النشر: | Portland Press Ltd., 2009. |
| سنة النشر: | 2009 |
| مصطلحات موضوعية: | 1303 Biochemistry, Molecular Sequence Data, 610 Medicine & health, CHO Cells, Mitochondrion, Biology, Endoplasmic Reticulum, Transfection, medicine.disease_cause, Biochemistry, Catalysis, Cell Line, Substrate Specificity, law.invention, 1307 Cell Biology, Cricetulus, Acetyl Coenzyme A, Acetyltransferases, law, Cricetinae, Databases, Genetic, 1312 Molecular Biology, medicine, Animals, Humans, Molecular Biology, Gene, Cells, Cultured, Neurons, chemistry.chemical_classification, Aspartic Acid, Mutation, Microscopy, Confocal, Base Sequence, Endoplasmic reticulum, Brain, Cell Biology, Molecular biology, Rats, Kinetics, Enzyme, nervous system, chemistry, Membrane protein, 10036 Medical Clinic, Recombinant DNA |
| الوصف: | The brain-specific compound NAA (N-acetylaspartate) occurs almost exclusively in neurons, where its concentration reaches approx. 20 mM. Its abundance is determined in patients by MRS (magnetic resonance spectroscopy) to assess neuronal density and health. The molecular identity of the NAT (N-acetyltransferase) that catalyses NAA synthesis has remained unknown, because the enzyme is membrane-bound and difficult to purify. Database searches indicated that among putative NATs (i.e. proteins homologous with known NATs, but with uncharacterized catalytic activity) encoded by the human and mouse genomes two were almost exclusively expressed in brain, NAT8L and NAT14. Transfection studies in HEK-293T [human embryonic kidney-293 cells expressing the large T-antigen of SV40 (simian virus 40)] indicated that NAT8L, but not NAT14, catalysed the synthesis of NAA from L-aspartate and acetyl-CoA. The specificity of NAT8L, its Km for aspartate and its sensitivity to detergents are similar to those described for brain Asp-NAT. Confocal microscopy analysis of CHO (Chinese-hamster ovary) cells and neurons expressing recombinant NAT8L indicates that it is associated with the ER (endoplasmic reticulum), but not with mitochondria. A mutation search in the NAT8L gene of the only patient known to be deficient in NAA disclosed the presence of a homozygous 19 bp deletion, resulting in a change in reading frame and the absence of production of a functional protein. We conclude that NAT8L, a neuron-specific protein, is responsible for NAA synthesis and is mutated in primary NAA deficiency (hypoacetylaspartia). The molecular identification of this enzyme will lead to new perspectives in the clarification of the function of this most abundant amino acid derivative in neurons and for the diagnosis of hypoacetylaspartia in other patients. |
| وصف الملف: | Molecular1.pdf - application/pdf |
| تدمد: | 1470-8728 0264-6021 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0a87a42c0a267892f586387055c62927Test https://doi.org/10.1042/bj20091024Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....0a87a42c0a267892f586387055c62927 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14708728 02646021 |
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